Despite advances in the treatment of patients with sepsis, sepsis remains the second most common cause of death in non-coronary intensive care units and the tenth leading cause of death overall in high-income countries. It has been estimated that >750,000 cases of severe sepsis occur annually in the United States, with a hospital mortality rate of ~35%. This number continues to grow annually. Nearly half of these septic patients develop severe sepsis and septic shock. In most hospitals more than 60% of severe sepsis patients present to the emergency department. Mortality increases along the sepsis continuum from approximately 25- 30% in severe sepsis and 40-70% in septic shock, and seems to be associated mainly with the amount of multi-organ failure. The goal of this SBIR Phase 1 application is to apply a new potentially life-saving therapy, Intrathoracic Pressure Regulation (IPR) recently developed and shown to increase circulation and survival rates in hemorrhagic shock and cardiac arrest, during the early resuscitation phase of sepsis. Based upon recent animal studies showing that non-invasive IPR can increase vital organ perfusion in states of severe hypotension, the goal of this research is to demonstrate proof of concept in a porcine model of septic shock that when IPR is applied during the initial hemodynamic stabilization treatment phase of sepsis, that key hemodynamic parameters will improve and short-term survival rates will increase. The new device is inserted within a standard respiratory circuit between the patient and a means to ventilate the patient. It functions by decreasing intrathoracic pressure during the expiratory phase to subatmospheric levels after each positive pressure ventilation. The decrease in intrathoracic pressure creates a negative pressure gradient between the thorax relative to the rest of the body thereby a) enhancing venous blood return to the heart b) increasing cardiac output and systemic arterial blood pressure, c) lowering right atrial and pulmonary artery pressures, and d) lowering intracranial pressure and thus further increasing cerebral perfusion pressure. The specific aims of this proposal include: 1) an animal study to demonstrate significant hemodynamic benefit and improved 24 hour survival in a porcine model of peritonitis, 2) an animal study to demonstrate that microcirculation, renal function, and cardiac function can be improved with IPR therapy, and 3) further design work to prototype a variable resistor to allow for adjustments in the intrathoracic vacuum achieved with the IPR and additional design work to prototype a secondary safety mechanism to prevent excessively low intrathoracic pressures by inadvertent user misuse. It is anticipated that a positive Phase 1 Study would provide sufficient preclinical data to support a Phase 2 grant application which would include a clinical trial. This potentially pioneering technology would serve in a complimentary manner with newer goal-directed resuscitation therapies to further reduce the currently excessively high morbidity and mortality for hundreds of thousands of American annually. In real terms, a potential 10% reduction in mortality relates could result in saving 50,000-100,000 lives annually in the United States alone. PUBLIC HEALTH RELEVANCE: Sepsis remains the second most common cause of death in non-coronary intensive care units and the tenth leading cause of death overall in high-income countries. It has been estimated that >750,000 cases of severe sepsis occur annually in the United States, with a hospital mortality rate of ~35%. The goal of this Phase 1 SBIR application is to determine whether the intrathoracic pressure regulator (ITPR), a novel device intended to increase circulation and blood pressure in states of significant hypotension, is a potential therapy for septic shock patients. This potentially pioneering technology would serve in a complimentary manner with newer goal-directed resuscitation therapies to further reduce the currently excessively high morbidity and mortality for hundreds of thousands of American annually. In real terms, a potential 10% reduction in mortality relates could result in saving 50,000-100,000 lives annually in the United States alone.